Dror Harats presents research on a new anti-inflammatory drug called CI-201 for treating atherosclerosis. In preclinical trials, CI-201 reduced progression of atherosclerosis by up to 92% and also showed effectiveness in treating rheumatoid arthritis and multiple sclerosis by reducing inflammatory markers. CI-201 works by mimicking oxidized phospholipids to modulate the immune system's inflammatory response. Phase I clinical trials are planned for 2006 to evaluate CI-201's safety and efficacy in humans.
Call Girls Nagpur Just Call 9907093804 Top Class Call Girl Service Available
New Anti-Inflammatory Therapy Reduces Atherosclerosis and Arthritis in Trials
1. Phospholipids Analogs as aPhospholipids Analogs as a
New Anti-Inflammatory Anti-New Anti-Inflammatory Anti-
Atherosclerosis TherapyAtherosclerosis Therapy
Dror HaratsDror Harats
The Institute of Lipids and Atherosclerosis Research,The Institute of Lipids and Atherosclerosis Research, ShebaSheba
Medical Center, Tel-Hashomer, & Vascular Biogenics LTD,Medical Center, Tel-Hashomer, & Vascular Biogenics LTD,
Israel.Israel.
Dallas TX, November 2005Dallas TX, November 2005
2. Confidential – November 2005
CI-201 SummaryCI-201 Summary
• Oral Small Molecule
• Anti-Atherosclerotic Anti-Inflammatory
• Reduces Progression Of Disease By Up To 92% In
Preclinical Trials
• Additional Proof of Concept In Rheumatoid Arthritis And
Multiple Sclerosis
• Phase I Clinical Trials In 2006
3. Confidential – November 2005
Target: Atherosclerosis
Meeting the Challenge of a Critical Clinical and Market Need
5. Confidential – November 2005
Atherosclerosis TimelineAtherosclerosis Timeline
FoamFoam
CellsCells
FattyFatty
StreakStreak
IntermediateIntermediate
LesionLesion AtheromaAtheroma
FibrousFibrous
PlaquePlaque
ComplicatedComplicated
Lesion/RuptureLesion/Rupture
Endothelial DysfunctionEndothelial Dysfunction
Smooth muscle
and collagen
From first decade From third decade From fourth decade
Growth mainly by inflammation and lipid accumulation Thrombosis,
inflammation
(Adapted from Stary et al. Circulation. 1995;92:1355.)
6. Confidential – November 2005
* Ross, R. Atherosclerosis, an inflammatory disease. N. Engl. J. Med. 1999, 340: 115 - 126
Atherosclerosis
Pathophysiology
Current solution
Abnormal Cholesterol
metabolism
Cholesterol build up
Statins
Only 30% decrease in events
Inflammatory
response*
Increased
plaque vulnerability
No current solution
Etiology
Current Treatments: Only Partial Solution
VBL’s Solution
CI-201
Option: Combination
Therapy
7. Confidential – November 2005
Plaque
growth
Plaque
destabilization
/ vulnerability
Plaque
Inflammation
Smaller & stable
plaque
Thrombus
Inflammatory
Cells
Few
SMCs Activated
Macrophages LesionSizemm2
x100
0
250
500
750
1000
0 Weeks 3 Weeks
oxLDL
Albumin
Control
P<0.01
CI-201: SM Ox-LDL Derivative to Address InflammationCI-201: SM Ox-LDL Derivative to Address Inflammation
CI-201 is a small molecule rationally designed to
mimic OxLDL epitopes
First proof of concept with OxLDL reducing
atherosclerosis by ~ 60%
OxLDL
8. Confidential – November 2005
CI-201 Inhibits Disease ProgressionCI-201 Inhibits Disease Progression
Atherosclerotic
Plaques
)%Base Line( -92%
6 month old Apo E KO mice; oral administration with CI-201 or PBS for 3 mos
Reduction in Plaques with CI-201 Treatment
9. Confidential – November 2005
With No Impact on MetabolismWith No Impact on Metabolism
Selected metabolic indices with & withoutSelected metabolic indices with & without
CI-201 treatmentCI-201 treatment
0
100
200
300
400
500
Body weight Cholesterol Triglycerides
PBS
CI 201 (0.1ug)
IL-10IL-10
IFNIFNγγ
ββ actinactin
PBSPBS CI-201CI-201
AortaAorta
IL-12IL-12
10. Confidential – November 2005
Oral
administrations
9day period
2weeksTime 0 4weeks
The effect of CI-201 Administration on Serum SolubleThe effect of CI-201 Administration on Serum Soluble
Inflammatory MarkersInflammatory Markers
ApoE mice were orally administered with CI-201 5 times every other day. Blood was collected beforeApoE mice were orally administered with CI-201 5 times every other day. Blood was collected before
oral administration began (time 0), 2 wks later (after oral administration period) and 4 wks lateroral administration began (time 0), 2 wks later (after oral administration period) and 4 wks later..
Blood collection
11. Confidential – November 2005
%frombaseline
IL-10 Serum Levels SAA Levels
%frombaseline
Control CI-201 Control CI-201
P<0.05)84%-3053%(
(100%-22,850%)
(100%-132%)
(30%-144%)
Baseline 14 days 28 days Baseline 14 days 28
days
Baseline 14 days 28 days Baseline 14 days 28
days
Anti-inflammatory effects of CI-201Anti-inflammatory effects of CI-201
%frombaseline
12. CI-201 Anti inflammatory EffectCI-201 Anti inflammatory Effect
Atherosclerosis
Mice Model
Rheumatoid Arthritis
Rat Model
Link: Inflammatory/immunologic responses
Prototype of autoimmune disease
CI 201CI 201
Anti inflammatory EffectAnti inflammatory Effect
Confidential – September 2005
13. Similarities Between Atherosclerosis and Rheumatoid Arthritis
Atherosclerosis Rheumatoid arthritis
Macrophage activation
↑ ↑
T-cell activation ↑ ↑
B-cell activation (oxLDL,
HSP Abs) none or ↑ none or ↑
CRP ↑ ↑
Adhesion molecules ↑ ↑
Possible antigens HSP, Ox-LDL, Infectious
agents
Collagen II, Cartilage
antigens, HSP, Infectious
agents
Confidential – September 2005
14. Confidential – November 2005
***
* P<0.05
** P<0.01
*** P=0.005
**** P<0.005
**** * **
** **** * *
*
Effect of CI-201 on Arthritic Score Adjuvant-induced RA Model
Treatment effected 65% reduction in paw swelling
ArthritisScore
15. CI-201 Treatment Attenuates Inflammatory Cells InfiltrationCI-201 Treatment Attenuates Inflammatory Cells Infiltration
Within The JointWithin The Joint
Lewis Male rats were orally treated with CI-201 before and after adjuvant induced arthritis.
Joints were collected on day 24 (arthritis peak) decalcified and stained with H&E.
Severe bone destruction (red arrows), new bone
formation and destruction of the synovial lining
(n=6).
No evidence of disease or mild
lymphocytic infiltrate (n=6)
CI-201Control
Confidential – September 2005
16. CI-201 (1,10µg/mouse) Treatment Decreased Clinical Signs of ArthritisCI-201 (1,10µg/mouse) Treatment Decreased Clinical Signs of Arthritis
Set of 5 oral administrations
every day
Confidential – September 2005
18. Confidential – November 2005
CI-201: Results SummaryCI-201: Results Summary
CI-201
Atherosclerosis Rheumatoid
Arthritis
Multiple
Sclerosis
IL-10
SAA
Atherosclerotic
Progression
92%
Cytokine
Marker
(Test in
Progress)
Clinical
Improvement
Paw Swelling
(65%)
Reduction of Inflammatory Markers Correlative to Reduction in Inflammatory Conditions
Cytokine
Marker
(Test in
Progress)
Preliminary
very
encouraging
results
19. Confidential – November 2005
Adapted from Witztum et al. Cell 104;503-516, 2001
AtherosclerosisAtherosclerosis
TNF-α
Via Immune
System
Direct Anti-
Inflammation
(other?)
20. Confidential – November 2005
CI-201 RadiolabelingCI-201 Radiolabeling
O
O
T
OH
O
T
OP
O
O-
O
N+
21. Confidential – November 2005
0
5000
10000
15000
20000
25000
4 8 15 26
Cell Lysate
Membrane
Cytosol
33
H oxPL Analog Uptake by Human monocytes (U937H oxPL Analog Uptake by Human monocytes (U937))
TotalDPM/Well
Time (hr)
22. Confidential – November 2005
Does oxLDL Compete with oxPL Analog on its Uptake byDoes oxLDL Compete with oxPL Analog on its Uptake by
MonocytesMonocytes??
0
500
1000
1500
2000
2500
3000
O
5ug/ml
25ug/ml
50ug/ml
DPM/Well
oxLDL
concentrations
No pre-
incubation
2hr pre-
incubation
(cells+oxLDL)
2hr pre-
incubation
(oxPL+oxLDL)
23. Confidential – November 2005
Cells Involved in the “GameCells Involved in the “Game””
Antigen presenting cells (APC)
B cells
Dendritic cells
Macrophages
Activated T-cells
Primary stimulation-Signal I
Secondary costimulation-Signal II
24. Confidential – November 2005
33
H oxPL Analog Uptake by Immune CellsH oxPL Analog Uptake by Immune Cells
DPM/Well
25. Confidential – November 2005
Anti-inflammatory Anti-atherogenic profile
within the plaque
ArbitraryUnits
P=0.005
P<0.05
CI-201, Induces
Anti-Inflammatory Response
CI-201 Anti-Inflammatory Response in AtherosclerosisCI-201 Anti-Inflammatory Response in Atherosclerosis
26. Confidential – November 2005
ObservationsObservations
• In all animal models tested hence; atherosclerosis, RA
and MS, IFN-γ was shown to be involved in disease
pathogenesis.
• Several lines of evidence that CI-201 reduces the level of
IFN-γ.
27. Confidential – November 2005
CI-201: Proposed Mechanism of Action ICI-201: Proposed Mechanism of Action I
APC
Thp
IFN-γ
Th1Th2
IL-4
IL-4
IL-10
CI-201
IL-12
IL-27
IL-18
28. Confidential – November 2005
CI-201: Proposed Mechanism of Action IICI-201: Proposed Mechanism of Action II
APC
Thp
IFN-γ
Th1Th2
IL-4
IL-4
IL-10
CI-201
T-bet
Stat-4 Jak-2
IL-12R
IL-12
IL-27
IL-18
29. Confidential – November 2005
HypothesisHypothesis
APC’s TNFα
CD40
IL10
INfγ
And ???
T cell
Atherosclerosis
MS
RA
Other Inflammatory
diseases
Inflammation
Ox-PL analog - CI-201
x
30. Confidential – November 2005
Summary of ResultsSummary of Results
• First-in-class anti-atherosclerotic / anti inflammatory drug
• Proof of concept in additional inflammatory diseases (RA, MS)
• Oral administration
• Effective at low doses
• Potentially synergistic application with Statins
• Safe – as shown by preliminary safety data
• Phase I Clinical Trials to begin Q2 2006
&lt;number&gt;
This graphic illustrates the history of plaque formation. Early lesions in the form of isolated macrophage foam cells may occur in infancy. Lipid accumulation can then lead to a fatty streak. Next, lipids accumulate in the extracellular space within the vessel wall. After age 30, an atheroma or visible lipid core may develop. Note that at this point, plaque growth is marked primarily by lipid accumulation. From age 40 on, we can see more fibrous plaques, which depend on the growth of a matrix of smooth muscle cells and collagen over the atheromatous core. Finally, if unstable, plaques may erode or rupture. Once the contents of the plaque are exposed to blood, platelet activation and thrombosis may occur.
Stary, et al. Circulation. 1995;92:1355-1374.